CAS 104987-11-3|LCP-Tacro|FK5|tacrolimus hydrate|Tacrolimus|FK-506|(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]...

General Information

Structure

Molecular Formula

C₄₄H₆₉NO₁₂

Molecular Mass

804.01816

Exact Mass

803.48197665

Charge

InChI

InChI=1S/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19+,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1

InChIKey

QJJXYPPXXYFBGM-LFZNUXCKSA-N

Canonic Smiles

C=CC[C@@H]1/C=C(\C)/C[C@H](C)C[C@H](OC)[C@H]2O[C@](O)([C@@H](C[C@@H]2OC)C)C(=O)C(=O)N2[C@H](C(=O)O[C@@H]([C@@H]([C@H](CC1=O)O)C)/C(=C/[C@@H]1CC[C@H]([C@@H](C1)OC)O)/C)CCCC2

Isomeric Smiles

C(=C\[C@@H]1CC[C@H]([C@@H](C1)OC)O)(/[C@@H]1[C@@H]([C@H](CC(=O)[C@@H](/C=C(\C)/C[C@H](C)C[C@@H]([C@@H]2[C@H](C[C@H]([C@](O2)(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1)C)OC)OC)CC=C)O)C)\C

Calculated Properties

JChem

Acid pKa

9.955601

H Acceptors

H Donor

LogD (pH = 5.5)

5.594105

LogD (pH = 7.4)

5.5929146

Log P

5.59412

Molar Refractivity

215.6203

Polarizability

84.94902

Polar Surface Area

178.36

Rotatable Bonds

Lipinski's Rule of Five

false

ALOGPS 2.1

Log P

3.19

LOG S

-5.3

Solubility (Water)

4.02e-03 g/l

Data Source

Academic Data

Commercial Catalog

Data Source

Names and Identifiers

Brand Name

LCP-TacroProtopicFujimycinPrograf

Synonyms

FK5tacrolimus hydrateTacrolimusFK-506TacarolimusK506tacrolimusPrografFK-506Fujimycin

IUPAC name

(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.0^{4,9}]octacos-18-ene-2,3,10,16-tetrone

IUPAC Traditional name

tsukubaenolide

Names and Identifiers

Registration numbers

PubChem SID

46506004160964205

CAS Number

104987-11-3

PubChem CID

445647445643

Registration numbers

Properties

Physical Property

Hydrophobicity(logP)

3.3

Solubility

Insoluble

DMSO

Safety Information

Storage Condition

-20°C

Product Information

Salt Data

Free Base

Properties

Related Proteins

No Data Available

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Molecular Spectra

No Data Available

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Molecule Details

DrugBank

DB00864

Drug Groups

approved; investigational

Description

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It was discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.

Indication

For use after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It was first approved by the FDA in 1994 for use in liver transplantation, this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.

Pharmacology

Tacrolimus is a macrolide antibiotic. It acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to cyclosporine studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporine. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment.

Toxicity

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD₅₀=134-194 mg/kg (rat).

Affected Organisms

Humans and other mammals

Biotransformation

Hepatic, extensive, primarily by CYP3A4. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.

Absorption

20% bioavailability; less after eating food rich in fat

Half Life

11.3 hours (range from 3.5 to 40.6 hours)

Protein Binding

75-99%

Elimination

In man, less than 1% of the dose administered is excreted unchanged in urine. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

Distribution

* 2.6±2.1 L/kg [pediatric patients]

Clearance

* 0.029 +/- 0.009 L/hr/kg [healthy subjects IV administered]
* 0.172 +/- 0.088 L/hr/kg [Healthy subjects administered PO]
* 0.138 +/- 0.071 L/hr/kg [liver transplantation pediatric patients]
* 0.038 +/-0.014 L/hr/kg [patients with renal impairment 0.02 mg/kg/4 hr, IV]
* 0.042 +/- 0.02 L/hr/kg [Mild Hepatic Impairment 0.02 mg/kg/4 hr, IV]
* 0.034 +/- 0.019 L/hr/kg [Mild Hepatic Impairment 7.7 mg PO]
* 0.017 +/- 0.013 L/hr/kg [Severe hepatic impairement 0.02 mg/kg/4 hr, IV]

References

• Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H: FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987 Sep;40(9):1249-55. [Pubmed]

• Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [Pubmed]

• Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. [Pubmed]

• Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K: Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient. Drug Metab Pharmacokinet. 2006 Apr;21(2):122-5. [Pubmed]

• Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ: Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S186-94. [Pubmed]

External Links

• [Wikipedia]

• [RxList]

• [Drugs.com]

Selleck Chemicals

S5003

Research Area: Immunology
Biological Activity:
FK-506 inhibits Ca2+-dependent transcription of lymphokine genes in T cells.FK-506 (0.1 to 300 nM) concentration dependently inhibited histamine release from lung parenchymal mast cells activated by anti-IgE. FK-506 was more potent in lung mast cells than in basophils (IC50 = 1.13 +/- 0.46 nM vs 5.28 +/- 0.88 nM; p less than 0.001), whereas the maximal inhibitory effect was higher in basophils than in lung mast cells (88.4 +/- 2.5% vs 76.4 +/- 3.8%; p less than 0.01). [2]FK-506 (1 to 300 nM) concentration dependently inhibited histamine release from basophils activated by Der p I Ag, anti-IgE, or compound A23187. FK-506 was more potent than CsA when basophils were challenged with Ag (IC50 = 25.5 +/- 9.5 vs 834.3 +/- 79.8 nM; p less than 0.001), anti-IgE (IC50 = 9.4 +/- 1.7 vs 441.3 +/- 106.7 nM; p less than 0.001), and A23187 (IC50 = 4.1 +/- 0.9 vs 36.7 +/- 3.8 nM; p less than 0.001). The maximal inhibitory effect of FK-506 was higher than that caused by CsA when basophils were activated by Der p I (80.0 +/- 3.6 vs 49.5 +/- 4.7%; p less than 0.001) and anti-IgE (90.4 +/- 1.8 vs 62.3 +/- 2.9%; p less than 0.001). [3]

Molecule Details

References

PubChem Literature

From Data Sources

• Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. Pubmed

• Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. Pubmed

• A de Paulis et al.J Immunol.1991; 146: 2374-2381

References

Bioactivity

PubChem BioAssay

Bioactivity

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General Information

Calculated Properties

• RDKit

• JChem

• ALOGPS 2.1

Data Source

• Academic Data

• Commercial Catalog

Names and Identifiers

• Brand Name

• Synonyms

• IUPAC name

• IUPAC Traditional name

Registration numbers

• PubChem SID

• CAS Number

• PubChem CID

Properties

• Physical Property

• Safety Information

• Product Information

Related Proteins

Molecular Spectra

Molecule Details

• DrugBank

• Selleck Chemicals

References

• PubChem Literature

• From Data Sources

Bioactivity

• PubChem BioAssay

Commercial Catalog

Selleck Chemicals

S5003

Brand Name

LCP-TacroProtopicFujimycinPrograf

Synonyms

FK5tacrolimus hydrateTacrolimusFK-506TacarolimusK506tacrolimusPrografFK-506Fujimycin

IUPAC name

IUPAC Traditional name

tsukubaenolide

PubChem SID

46506004160964205

CAS Number

104987-11-3

PubChem CID

445647445643

Physical Property

Hydrophobicity(logP)

3.3

Solubility

Insoluble

DMSO

Safety Information

Storage Condition

-20°C

Product Information

Salt Data

Free Base

DrugBank

DB00864

Drug Groups

approved; investigational

Description

Indication

Pharmacology

Toxicity

Affected Organisms

Humans and other mammals

Biotransformation

Absorption

20% bioavailability; less after eating food rich in fat

Half Life

11.3 hours (range from 3.5 to 40.6 hours)

Protein Binding

75-99%

Elimination

In man, less than 1% of the dose administered is excreted unchanged in urine. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.

Distribution

* 2.6±2.1 L/kg [pediatric patients]

Clearance

References

• Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [Pubmed]

• Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. [Pubmed]

External Links

• [Wikipedia]

• [RxList]

• [Drugs.com]

Selleck Chemicals

S5003

From Data Sources

• Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. Pubmed

• Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. Pubmed

• A de Paulis et al.J Immunol.1991; 146: 2374-2381

Molecule

ID:742